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In the year 1968, every day is the same for Dr. Robert Morgan (Price): he wakes up, gathers his weapons, and then goes hunting for vampires. Morgan lives in a world where everyone else has been infected by a plague that has turned them into undead, vampiric creatures that cannot stand sunlight, fear mirrors, and are repelled by garlic. They would kill Morgan if they could, but they are weak and unintelligent. At night, Morgan locks himself inside his house; during the day, he kills as many vampires as he can, burning the bodies.

A flashback sequence explains that, three years before, Morgan's wife and daughter had succumbed to the plague, before it was widely known by the public that the dead would return to life. Instead of taking his wife to the same public burn pit used to dispose of his daughter's corpse, Morgan buried her without the knowledge of the authorities. When his wife returned to his home and attacked him, Morgan became aware of the need to kill the plague victims with a wooden stake. Morgan hypothesizes that he is immune to the bacteria because he was bitten by an infected vampire bat when he was stationed in Panama, which introduced a diluted form of the plague into his blood.

One day, a dog appears in the neighborhood. Desperate for companionship, Morgan chases after the dog but does not catch it. Sometime later the dog appears, wounded, at Morgan's doorstep. He takes the dog into his home and treats its wounds, looking forward to having company for the first time in three years. He quickly discovers, however, that it, too, has become infected with the plague. Morgan is later seen burying the dog, which he has impaled with a wooden stake.

After burying the dog, Morgan spots a woman in the distance. The woman, Ruth, is terrified of Morgan at first sight and runs from him. Morgan convinces her to return to his home but is suspicious of her true nature. Ruth becomes ill when Morgan waves garlic in her face but claims that she has a weak stomach.

Morgan's suspicion that Ruth is infected is confirmed when he discovers her attempting to inject herself with a combination of blood and vaccine that holds the disease at bay. Ruth initially draws a gun on Morgan but ultimately surrenders it to him. Ruth then tells him that she is part of a group of people like her — infected but under treatment — and was sent to spy on Morgan. The vaccine allows the people to function normally with the drug in the bloodstream, but once it wears off, the infection takes over the body again. Ruth explains that her people are planning to rebuild society as they destroy the remaining vampires, and that many of the vampires Morgan killed were technically still alive. Ruth desperately urges Morgan to flee, but he inexplicably refuses.

While Ruth is asleep, Morgan transfuses his own blood into her. She is immediately cured, and Morgan sees hope that, together, they can cure the rest of her people. Moments later, however, Ruth's people attack. Morgan takes the gun and flees his home while the attackers kill the vampires gathered around Morgan's home.

Ruth's people spot Morgan and chase him. He exchanges gunfire with them and picks up tear gas grenades from a police station armory along the way. While the tear gas delays his pursuers somewhat, Morgan is wounded by gunfire and retreats into a church. Despite Ruth's protests to let Morgan live, his pursuers finally impale him on the altar with a spear. With his dying breaths, Morgan denounces his pursuers as "freaks" and declares that he is the last true man on Earth.

Lippert had wanted to make a "last man on earth" type film for a while. In the late 1950s Charles Marquis Warren and Robert Stabler optioned a novel by science fiction writer George Stewart called Earth Abides. Harry Spalding, who worked for Lippert, said the release of The World, the Flesh and the Devil (1959) killed off plans for that project. Spalding then read Matheson's novel and suggested Lippert film that book instead.[4] The project was announced in August 1962.

Lippert originally told Matheson that Fritz Lang would direct the film, and Matheson thought that would be "wonderful". Eventually, however, Sidney Salkow was chosen to direct. Matheson made the follow up comment: "Well, there's a bit of a drop."[5]

To save money, the film was shot in Italy with a predominantly Italian cast and crew.[6]

Matheson later said the film was the most faithful adaptation of his book, but called the result "inept" and used a pen name for his screenplay. (He later said he thought Harrison Ford as star and George Miller as director would have been the ideal combination.")[5]

The film is different from the novel on which it is based, in multiple ways:

The protagonist of the novel is named Robert Neville, not Robert Morgan

The protagonist's profession is changed a from plant worker to scientist

The vampires are almost zombie-like, whereas in the novel, they are fast, and capable of running and climbing

The dog that shows up on Neville's doorstep in the novel is timid and comes and goes as it pleases, in contrast to the dog in the film

The relationship with Ruth slightly differs in the novel, in that no transfusion takes place; a cure seems implausible, even as Neville hopes he will find one; and Ruth escapes after Neville discovers that she is infected

In the novel, Neville is not captured until many months later, and even then he barely fights

The novel ends shortly before Neville is to be executed; Ruth returns to give him suicide pills and finds it ironic that he has become as much of a legend to the new society as vampires once were to Neville's world (hence the title)

The novel implies that the vampire plague resulted from a biological disease; the origin of the disease is never explained in The Last Man on Earth (and is altered in the subsequent adaptations)

Although the film was not considered a success upon its release, it later gained a more favorable reputation as a classic of the genre.[7] As of November 2011, The Last Man on Earth holds a 71% rating on Rotten Tomatoes.[8]Phil Hall of Film Threat called The Last Man on Earth "the best Vincent Price movie ever made."[7]

Among the less favorable reviews, Steve Biodrowski of Cinefantastique felt the film was "hampered by an obviously low budget and some poorly recorded post-production dubbing that creates an amateurish feel, undermining the power of its story",[9] while Jonathan Rosenbaum of the Chicago Reader remarked, "Some would consider this version better than the 1971 remake with Charlton Heston, The Omega Man, but that isn't much of an achievement."[10]

Among the film's creators, Price "had a certain fondness for the film" and felt it was better than The Omega Man.[9]Richard Matheson co-wrote the film's screenplay, but was unhappy with the results. To keep receiving residual income from the film, though, he had to be credited, so he used the name "Logan Swanson" - a combination of his wife's mother's maiden name and his mother's maiden name.[11] Matheson said: "I was disappointed in the film, even though they more or less followed my story. I think Vincent Price, whom I love in every one of his pictures that I wrote, was miscast. I also felt the direction was kind of poor. I just didn’t care for it."[12]